tbuckley/cabot-search huggingface dataset:
US Preventive Services Task Force Recommendation Statement on Screening for Atrial Fibrillation
Authors: Tarryn Tertulien, Quentin R. Youmans, Utibe R. Essien
Journal: JAMA (2022)

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Mini-Cog to predict postoperative delirium in patients who underwent Transurethral Resection of Bladder Tumor (TURBT) under spinal anesthesia
Authors: S. Yajima, Y. Nakanishi, N. Okubo, S. Matsumoto, K. Tanabe, M. Kataok, H. Masuda
Journal: European Urology (2022)
LGG-55. Autophagy sensitizes CNS tumors to targeted therapy by lowering their apoptotic threshold
Authors: Michele Crespo, Shadi Zahedi, Andrew Morin, Darya Wodetzki, Cecilia Caino, Jean Mulcahy Levy
Journal: Neuro-Oncology (2022)

Abstract Autophagy inhibition improves the effectiveness and overcomes RAF pathway inhibition (RAFi) resistance across multiple CNS tumors and molecularly distinct resistance mechanisms. Mechanistic links between autophagy and apoptotic cell death may explain this ability to improve RAFi response and reverse resistance. RAFi sensitive (MAF 794, AM38) and resistant (MAF 794R, MAF 905-3, AM38R, B76) BRAFV600E CNS tumor cell lines were analyzed at baseline, following RAFi (vemurafenib), autophagy inhibition (chloroquine or shRNAs), and combination therapy. Growth assays and caspase activation were monitored by Incucyte Zoom. qRT-PCR evaluated key pro-apoptotic BH3-only members of the BCL-2 family. Broad BH-3 profiling was completed using the Letai JC-1 Plate-Based protocol. Western blot analysis assessed protein levels. Combination pharmacologic treatment caused alterations in key pro-apoptotic BH3-only proteins including an increase in BNIP3L and PUMA. Genetically inhibiting autophagy with shRNAs for ATG5 and ATG7 (proteins required for formation of the autophagosome) produced similar results with increases in both protein and mRNA levels of BNIP3L and PUMA following RAFi treatment. This suggested autophagy-mediated regulation of BH3 proteins functions to determine cellular apoptotic threshold. Caspase activation demonstrated increased effectiveness of combined RAFi and autophagy inhibition overcoming the apoptotic threshold compared to single drug treatment. BH3 profiling demonstrated a dependence on BCL-2 to inhibit apoptosis. BH3 mimetics competitively bind to pro-survival BCL-2 family members, blocking their protective effects and pushing tumor cells towards apoptosis. Autophagy inhibition can also improve treatment response by overcoming the apoptotic threshold in RAFi resistant cells and magnifying the apoptotic response in sensitive cells. BH3 profiling reveals CNS BRAFV600E are BCL-2 dependent cells, unprimed for apoptosis, which may be good candidates for additional treatment with BH3 mimetics such as venetoclax. This presents an attractive treatment for MAPK activated CNS tumors by enhancing apoptotic cell death by targeting the MAPK pathway, autophagy and BH3.
Racial disparities affecting Black patients with diffuse large B-cell lymphoma.
Authors: Daniel Arthur Ermann, Victoria Vardell, Lindsey Fitzgerald, Harsh Shah, Deborah Marie Stephens, Boyu Hu
Journal: Journal of Clinical Oncology (2022)

7507 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma, with the majority of patients (pts) achieving long-term survival due to the curative nature of frontline therapy. However, limited data exists regarding presentation and clinical outcomes for underrepresented minorities. In this study, we aimed to evaluate the influence of racial identity on overall survival (OS) outcomes for DLBCL pts. Methods: The National Cancer Database was used to identify DLBCL pts diagnosed from 2004-2018. Demographic and treatment characteristics were compared between racial groups. Kaplan-Meier and Cox regression analyses were used to compare OS between Black and white populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, co-morbidity score, median income, and insurance status. Results: Of 223,709 DLBCL pts, 87% were white, 8% Black, and 5% other. As compared to white pts at diagnosis, Black pts were younger (mean 56 years [SD ± 16] vs. 66 years [SD ± 15]), more likely to have ≥1 co-morbidity (33% vs. 27%), be HIV-positive (26% vs. 5%), and have both B-symptoms (40% vs. 30%) and stage IV disease (42% vs. 37%) (All p&lt;0.001). In terms of socioeconomic demographics, Black pts were more likely to be uninsured (8% vs. 3%) and be in the lowest median income quartile (43% vs. 15%), but were more likely to receive treatment at academic centers (50% vs. 36%) (all p&lt;0.001). Both Black and white pts had similar IPI scores at diagnosis and were equally likely to receive multi-agent chemotherapy (77% vs. 77%, p&lt;0.001). With a median follow up of 44.9 months, median OS for all treated HIV-negative DLBCL pts was 109 months (range 21-197). Compared to age-matched white pts, Black pts age ≤ 60 had worse median OS (46 vs. 76 months) along with 5- (73% vs. 75%) and 10-year OS (65% vs. 69%) (all p &lt;0.001). Similar results were seen for Black and white pts between the ages of 61-79, but these differences were not demonstrated for pts ≥80 years old (Table). On multivariate analysis, Black race was independently associated with worse OS (HR 1.06, CI 1.01-1.10, p=0.02). Interestingly, the propensity matched analysis demonstrated no significant OS difference between Black and white pts (median 127 vs. 117 months; HR 1.0, CI 0.94-1.06; p=0.90). Conclusions: We present the largest study to date examining racial disparities in DLBCL. This data demonstrates that Black patients have significantly shorter OS compared to white patients, which persists on multivariate analysis. However, this disparity in survival became nonsignificant when patients are equally matched on surrogate markers of healthcare access such as insurance status and median income. Further studies into examining these racial differences are warranted to optimize care for all DLBCL patients. [Table: see text]
Association between TP53, PAR1 and CCR5 gene polymorphisms and non-small cell lung cancer susceptibility in the Amazon.
Authors: Esdras Edgar Batista Pereira, Williams Fernandes Barra, Marianne Rodrigues Fernades, Juliana Carla Gomes Rodrigues, Antônio André Conde Modesto, Bruno Melo Fernandes, Lucas Favacho Pastana, Rommel Mario Rodriguez Burbano, Paulo Pimentel Assumpção, João Farias Guerreiro, Sidney Emanuel Batista dos Santos, Ney Pereira Carneiro dos Santos
Journal: Journal of Clinical Oncology (2022)

e20538 Background: Lung cancer is one of the most frequent neoplasms in the world, representing 11.4% of all registered cancers, and is responsible for 18% of cancer deaths. It is divided into two categories, small cell lung cancer, responsible for 15% of cases; and non-small cell lung cancer (NSCLC), which represents 85% of cases. The most well-known risk factor for the development of lung cancer is smoking, due to substances contained in tobacco associated with inflammation and carcinogenesis. Pulmonary carcinogenesis is a complex and gradual process, with synergistic and complex interactions between environmental risk factors and individual genetic susceptibility. The aim of this study was to investigate possible associations between TP53, PAR1, and CCR5 gene polymorphism for susceptibility to NSCLC in the Amazon. Methods: This is a pilot, case-control study, which included 263 subjects, 67 patients with NSCLC and 196 healthy subjects. The samples were analyzed for TP53 (rs17880560), PAR1 (rs11267092), and CCR5 (rs333) gene polymorphism, genotyped in PCR, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between individuals with and without lung cancer. Results: We observed that some genotypes were associated with protection for NSCLC: TP53 gene LED/DEL genotype (p = 0.041, OR: 0.510, 95%CI: 0.267-0.974); DEL/DEL genotype of the PAR1 gene (p = 0.023, OR: 0.471, 95%CI: 0.247-0.971); and also the INS/INS genotype of the CCR5 gene (p = 0.033, OR: 0.331, 95%CI: 0.120-0.917). Conclusions: TP53 (rs17880560), PAR1 (rs11267092) and CCR5 (rs333) gene variants were significantly associated with NSCLC in patients from the Amazon. The validation of these findings may favor, in the future, the screening of individuals, facilitating the institution of preventive measures personalized, early diagnosis, consequently reducing the cost for health services and mortality from this malignant neoplasm. Keywords: Genetic Polymorphism; TP53; PAR1; CCR5; Biomarker; Non-Small Cell Lung Cancer.
Using electronic health records to derive a synthetic control arm for a historical trial on relapsed/refractory multiple myeloma.
Authors: Alessandra Bisquera, Jamie Wallis, Ray Valencia, David Ruau, Nicholas Scott-Ram, Lewis Carpenter
Journal: Journal of Clinical Oncology (2022)

e20025 Background: It is increasingly challenging and ethically questionable to recruit patients on control arms when a vast body of information is readily available through electronic health records (EHR). Synthetic Control Arms (SCA) may reduce the time and cost of running a trial, and ultimately alleviate patient burden. This study explores the potential of SCAs derived from EHR to provide additional support for trials investigating treatment efficacy in multiple myeloma (MM). Methods: De-identified EHR from a UK NHS trust were matched with patients from a historical, Phase III randomised control trial investigating the efficacy of elotuzumab therapy in combination with lenalidomide and low-dose dexamethasone in relapsed/refractory MM (ClinicalTrials.gov Identifier: NCT01239797). Trial specific eligibility criteria were applied to the EHR dataset to derive 94 patients for the SCA. The primary outcome was progression free survival (PFS), as defined by the International Myeloma Working Group based on relative and absolute changes in serum M protein or kappa/lambda free light chain assay. The observation period was defined as time from randomisation (Trial) or treatment initiation (SCA) to death or disease progression. Results: In the SCA, the median age was 72 years [range 41, 93], 44% female, 76% white ethnicity, between 1 to 3 prior therapies, and between 0 to 6.3 years since diagnosis. This is in comparison to the trial control arm (n = 325) with a median age of 66 years [range 38, 91], 41% female, 86% white ethnicity, 1 to 4 prior therapies, and 0 to 16.2 years since diagnosis. Median PFS in the SCA was 14.4 months (95% Confidence Interval (CI) 9.5, 22.2), compared to 14.9 months (95% CI 12.1, 17.2) in the trial control arm. The hazards of progression or death in the trial treatment arm (when compared to trial control) was 0.70 (95% CI 0.57, 0.85) and 0.71 (95% CI 0.54, 0.95) when compared to the SCA. Additional sensitivity analysis using Multiple Imputation of missing ECOG values in the SCA yielded similar results, with a median PFS of 16.5 months (95% CI 10.4, 24.0) and hazards that is 0.77 (95% CI 0.57, 1.05) lower in the treatment arm. Conclusions: These results show that SCA can generate valuable additional evidence of efficacy supporting regulatory submission with considerable benefits in term of budget and time. Future work on SCAs aim to further refine the precision of estimates by applying the best performing confounder adjustment techniques.
Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial.
Authors: Sana Intidhar Labidi-Galy, Manuel Rodrigues, Jose L. Sandoval, Jean Emmanuel Kurtz, Florian Heitz, Anna Maria Mosconi, Ignacio Romero, Regina Berger, Shoji Nagao, Ignace Vergote, Gabriella Parma, Trine Jakobi Nøttrup, Etienne Rouleau, Georges Garnier, Ahmed El-Balat, Claudio Zamagni, Cristina Martín-Lorente, Eric Pujade-Lauraine, Alice Fiévet, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2022)

5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]
Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants
Authors: Behnood Bikdeli, Farbod Zahedi Tajrishi, Parham Sadeghipour, Azita H. Talasaz, John Fanikos, Giuseppe Lippi, Deborah M. Siegal, John W. Eikelboom, Manuel Monreal, David Jimenez, Jean M. Connors, Walter Ageno, Geoffrey D. Barnes, Gregory Piazza, Dominick J. Angiolillo, Sahil A. Parikh, Ajay J. Kirtane, Renato D. Lopes, Deepak L. Bhatt, Jeffrey I. Weitz, Roxana Mehran, Harlan M. Krumholz, Samuel Z. Goldhaber, Gregory Y. H. Lip
Journal: JAMA Cardiology (2022)

Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.
Can prostate biopsy be avoided in all patients with negative MRI? Results of a multicentric study
Authors: T.A. Nguyen, O. Cussenot, G. Fiard, A. Fourcade, C. Deruelle, V. Tissot, G. Cancel Tassin, J.B. Le Francq, L. Doucet, G. Fournier, A. Valeri
Journal: European Urology (2022)
MUTYH-related polyposis syndrome associated with a variant of uncertain significance mutation: A new pathogenic mutation?
Authors: Clarissa Gondim Picanço-Albuquerque, Rosane Oliveira Sant'Ana, Maria Claudia dos Santos Luciano, Maria Júlia Barbosa Bezerra, Flávio da Silveira Bitencourt, Francisca Fernanda Barbosa Oliveira, Thuany Pinto Rocha de Souza, Paulo Goberlânio de Barros Silva, Marcos Venício Alves Lima, Isabelle Joyce de Lima Silva-Fernandes
Journal: Journal of Clinical Oncology (2022)

e22528 Background: The familiar history is indispensable to clinical investigation during genetic counseling and the new molecular techniques allowed the identification of hereditary cancer predisposition syndromes (CPS). However, the classification systems of these syndromes are difficulty and very complex. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases to reduce the subjectivity bias of mutation variants classified as risk. Methods: To show the difficulty of classification of these variants we describe a case report of a family from countryside of Brazil in which there is a high rate of inbreeding. This family has three brothers with polyposis and colorectal cancer between 51 and 60 years-old. Results: The index-case had multiple polyps, developed colorectal cancer at 51 years-old and had a familiar history of two brother dead by colorectal cancer after polyposis and nine brother without familiar history of cancer, a father dead at 38 years-old by non-specific lung-disease and a mother alive at 83 years-old. There was no description of other cases of cancer among uncles and grandparents. The index-case performe a NSG genetic painel to CPS and showed a homozygosis variant in MUTYH gene: NM_001048174.1: c.253T &gt; C:p.(Trp85Arg), that was classified as variant of uncertain significance (VUS). MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors and may be considered a cell protective factor and is associated with MUTYH-related polyposis (MAP). MAP is an autosomal recessive CPS and presents a phenotype that overlaps attenuated polyposis and familial adenomatous polyposis, increasing the risk of colorectal cancer in 43-63% up to 60 years or 80% if there is no surveillance/tracking. In view of the family history that suggests autosomal recessive inheritance, with a homozygous variant absent in the database of population controls (gnomAD) and in which in silico predictors indicate the effect of this variant as deleterious, the management of this family must be carried out considering it as a potential high-risk pathogenic variant. Conclusions: While the classification criteria for the variants are being refined, we reinforce the importance of a careful family history in the approach to CPS in order to offer an appropriate clinal conduct in the prevention of hereditary cancer.
Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis
Authors: Richard J Allen, Amy Stockwell, Justin M Oldham, Beatriz Guillen-Guio, David A Schwartz, Toby M Maher, Carlos Flores, Imre Noth, Brian L Yaspan, R Gisli Jenkins, Louise V Wain
Journal: Thorax (2022)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk.